Thrombin receptor is activated by the cleavage of its N-terminal domain by thrombin, which generates a new amino terminus. This acts as a tethered ligand, activating the receptor. The first six of the amino acids of the new N-terminus are sufficient to define agonist activity. However, small peptides are very flexible and likely to adopt a number of unproductive structures (i.e., those that don't bind the receptor). Thus, there is a considerable entropic penalty to pay for the binding of small peptides. I am synthesizing a series of cyclic peptides to restrict the accessible conformational space. By covalently connecting two side chains, either as a disulfide or a lactam, the peptide is forced to be more rigid. The accessible space can be changed by varying the ring size. In order to correlate these structures with measured agonist activity, I will model these compounds in the Computer Graphics Lab, visualize the structures, and compare the good agonists with those that are not as effective. This may suggest ways to make further improvements, and may eventually help define a pharmacophore. The structure of particularly interesting agonists will be determined by NMR, which will also require use of molecular dynamics and display software.